Viral respiratory tract infections have been implicated in the pathogenesis of childhood asthma,but responsible mechanisms either related to host susceptibility or virulence patterns of specific viruses remain unestablished. This Program Project Grant renewal application will expand on a novel unsuspected finding during the current funding period: infants who wheeze with rhinovirus (RV) (the common cold virus) during infancy are significantly at risk for developing childhood asthma. We therefore hypothesize that RV infections during childhood and adolescence contribute significantly to childhood wheezing and asthma inception/exacerbation due to abnormal host innate immune responses and/or based on the virulence patterns of specific strains of rhinovirus producing these illnesses. Moreover, these abnormal responses to rhinovirus infections may be further modulated by the host's stage of development (infancy, childhood, and adolescence), gender, and gene by environment interactions. The components of this PPG application, both multidisciplinary and integrated, include 4 projects and 3 cores. Project I will continue comprehensive phenotypic characterization of the cohort that has been and will be the primary resource for data acquisition related to viral epidemiology, molecular virology, molecular biology, and genetic studies involving Project IIIV and the Virology Core. Further, it will evaluate host susceptibility to viral infections that are related to deficiencies in interferon responses within various tissue compartments. Project II will establish if specific RV serotypes or other respiratory pathogens are more likely to induce wheezing illnesses and asthma and the molecular basis for these increased virulence patterns. Project III will analyze mechanisms involved in RVregulated intracellular signaling pathways in both monocyte/macrophages and airway epithelial cells that underlie host susceptibility to RV-induced asthma. Project IV will focus on genes involved in RV pathways, study the mechanisms underlying the observed gene-environment interactions with RV infection and sex, and further characterize the role of micro RNAs in modulating variable responses to RV infection and the subsequent risk for asthma. RELEVANCE: This grant will define mechanisms by which viral infections impact on the clinical expression of childhood asthma that will be relevant for the development of therapies aimed at both acute treatment (anti-viral medications) and primary prevention (vaccines).